Osteoporosis affects millions of patients each year in the U.S. The clinically available agents, currently used to treat osteoporosis and bone fragility syndrome, are still limited. Estrogen loss at menopause and during aging leads to accumulation of reactive oxidant species (ROS). Mechanical unloading during long term bed rest or space flight also increase intracellular ROS production and cause bone loss. Although antioxidants, such as nitric oxide donor nitroglycerin and N-acetyl-cysteine have shown some positive effects on estrogen deficiency or unloading induced bone loss, no potent antioxidants have been developed to target on bone metabolic diseases. We have recently identified a novel target that regulates anti-oxidative response and is involved in load-induced osteogenesis and bone homeostasis. The novel target is nuclear factor erythroid 2-related factor 2, known as Nrf2. Several previous studies including ours have shown Nrf2 helps to preserve bone mass during normal and disease conditions. Recently, a synthetic Nrf2 activator, Bardoxolone Methyl (BARD), which has been used to treat diabetes associated atherosclerosis and diabetic chronic kidney diseases in animal models, is currently in Phase III clinical trials. Our long-term goal is to determine whether targeting Nrf2 by pharmacological intervention can be used to treats osteoporosis. Our preliminary findings leading to this application support the hypothesis that Nrf2 activation in osteocytes by pharmacological intervention may prevent or restore bone loss caused by unloading or estrogen deficiency through reducing ROS. We propose the following two specific aims using C57BL/6 mice as well as the Nrf2-/- floxed mice bred with Col2.3kB Col1?1-Cre or DMP1-8kb-Cre mice toward deletion of Nrf2 in osteoblastic cells or osteocytes, respectively. We will determine whether activation of Nrf2 by pharmacological intervention prevents or restores bone loss in unloading or estrogen deficient conditions; We will also determine the cellular and molecular mechanisms of Nrf2 signaling in skeletal tissues. Successful completion of this project will demonstrate potential of Nrf2 activator used to treat osteoporosis and identify the bone cells responsible for Nrf2-mediated mechanisms involved in bone formation. The project will further provide new insights in mechanosensitivity of bone cells and skeletal adaptation, and has potential to discover novel targets for osteoporosis therapy.